If the healthcare community hopes to head off the impending cancer storm, we need to get more serious about cancer prevention soon. Unfortunately, less than 1.5% of total biomedical research funding is targeted to early detection and prevention of chronic disease. With respect to all human malignancies, 35% are linked directly to diet and an additional 14-20% to obesity. Consistent with these data, cancer risk can be lowered by 36% when humans adhere to healthy dietary principles. Establishing a causal role for cancer dietary chemoprevention approaches that are free of safety problems intrinsic to drugs administered over long periods of time would have a major translational impact in cancer prevention and patient survivorship. Therefore, our overall goal is to better understand the molecular (nuclear and plasma membrane targeted) mechanisms linking intestinal epithelial cell responses to diet-derived natural botanical products, and endogenous (gut microbial) modifiers of colon cancer risk. Our extensive experience in the dietary chemoprevention field has afforded us with a unique mechanistic perspective in this regard. We propose to pursue two novel research themes. Project 1 will assess the combined agonist and antagonistic role of Arylhydrocarbon Receptor (AhR) ligands as determinants in colon stem cell homeostasis and malignant transformation. Our studies to date indicate that AhR ligands have profound short-term effects on stemness, and may be beneficial in terms of malignant transformation. Project 2 is designed to determine whether by altering cell membrane liquid ordered nanoscale assemblies, and therefore protein spatial localization and signaling, that select amphiphilic dietary agents will reduce oncogenic K-Ras signaling leading to reduced tumorigenesis. This strategy is consistent with recent reports from our lab and others that select amphiphilic agents, through direct modulation of the biophysical properties of the plasma membrane, alter oncogenic K- Ras nanoclustering and suppress signal transduction.